Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice

Xinhua Yan, Robert L. Price, Masaharu Nakayama, Kenta Ito, Adam J.T. Schuldt, Warren J. Manning, Atsushi Sanbe, Thomas K. Borg, Jeffrey Robbins, Beverly H. Lorell

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light-chain (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (LV) systolic pressure and peak +dP/dt were depressed while LV diastolic pressure was elevated (P < 0.05). Echocardiography showed severely depressed LV fractional shortening, increased systolic and diastolic dimensions, and wall thinning (P < 0.05). Confocal and electron microscopy studies revealed an increase in the size of myocytes and interstitial spaces as well as an increase in interstitial collagen, disruption of the Z-band, and changes in cytochrome c localization. The changes were most prominent in the highest-expressing TG line, which implies a dose-response relationship. AT 2 overexpression was also directly associated with the increase of phosphorylated protein levels of PKC-α, PKC-β, and p70S6 kinase. These data demonstrate that ventricular myocyte-specific expression of AT 2 receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.

Original languageEnglish
Pages (from-to)H2179-H2187
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume285
Issue number5 54-5
DOIs
Publication statusPublished - 2003 Nov

Keywords

  • Cardiac disease
  • Myocyte
  • Myosin light-chain promoter

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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